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The advancing validation and exploitation of CSF and blood neurofilament light chain protein as a biomarker of neuroaxonal damage has deeply changed the current diagnostic and prognostic approach to neurological diseases. Further, recent studies have provided evidence of potential new applications of this biomarker also in non-primary neurological diseases. In the present review we summarize the state of the art, future perspectives, but also limitations, of neurofilament light chain protein as a CSF and blood biomarker in several medical fields, including intensive care medicine, surgery, internal medicine and psychiatry. In particular, neurofilament light chain protein is associated with the degree of neurological impairment and outcome in patients admitted to intensive care units or in the perioperative phase and it seems to be highly interconnected with cardiovascular risk factors. Beyond that, interesting diagnostic and prognostic insights have been provided by the investigation of neurofilament light chain protein in psychiatric disorders as well as in the current coronavirus disease-19 pandemic and in normal ageing. Altogether, current data outline a multifaceted applicability of CSF and blood neurofilament light chain protein ranging from the critical clinical setting to the development of precision medicine models suggesting a strict interplay between the nervous system pathophysiology and the health-illness continuum., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A β 42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A β 42/A β 40 ratio. We compared CSF A β 42 and A β 42/A β 40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death., Methods: We measured CSF A β 40 and A β 42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease ( n  = 159), AD ( n  = 12), dementia with Lewy bodies (DLB, n  = 4), AD/DLB mixed pathologies ( n  = 5), and various other pathologies ( n  = 31)., Results: The score reflecting the severity of A β pathology showed a better correlation with ln(A β 42/A β 40) ( R 2  = 0.506, β  = -0.713, P  < 0.001) than with ln(A β 42) ( R 2  = 0.206, β  = -0.458, P  < 0.001), which was confirmed after adjusting for covariates. A β 42/A β 40 ratio showed significantly higher accuracy than A β 42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with A β 42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut-off value of 0.810, the analysis of A β 42/A β 40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology., Interpretation: The present data support the use of CSF A β 42/A β 40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A β pathology burden, and its introduction in the research diagnostic criteria for AD., Competing Interests: Nothing to report.

According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.